Obesity has reached an epidemic stage and created serious public health problems in the United States. Genetic factors are strongly involved in the development of obesity, most likely in the form of interactions of multiple genes with obesity-promoting environments, such as high fat diets. The present proposal focuses on the identification of pathophysiological mechanisms that could point to the cause of obesity mediated by an obesity susceptibility locus, tabw2, and its molecular basis which is responsible for fat mass accretion that is exaggerated by feeding high fat diets. Previously, we have mapped a quantitative trait locus (QTL) linked to body weight on mouse chromosome 6 in a cross between C57BL/6J (B6) and obese diabetic TALLYHO/JngJ (TH) mouse strains. The TH allele was associated with higher body weights, and the QTL is named tabw2 (TALLYHO Associated Body Weight 2). Subsequently, we have constructed a congenic strain that carries a TH-derived genomic segment containing tabw2 on a B6 background. This congenic strain of mice (tabw2 mice) exhibits increased adiposity, hyperleptinemia, hypertrophied adipocytes, increased lipogenesis, and dampened diurnal rhythms of circulating leptin levels. Upon high fat diet feeding, the obesity in tabw2 mice becomes exacerbated, followed by developing insulin resistance. Based on our preliminary data, we hypothesize that a TH allelic difference at tabw2 locus confers susceptibility to obesity that is magnified by high fat diets. In order to test this hypothesis we propose the following specific aims: Aim 1, investigate mechanisms of energy partitioning in tabw2 mediated obesity on low- and high-fat diets;Aim 2, fine map the tabw2 interval using nested recombinant subcongenic lines and haplotype mapping;Aim 3, identify the molecular basis of the tabw2 gene(s). At the successful conclusion of this work, the pathogenic mechanisms leading to an excess fat mass mediated by the tabw2 mutation(s) and the potential role of dietary fat in the development and progression of the condition will be elucidated. We will have identified the tabw2 gene(s) which when mutated causes obesity that is exacerbated by high fat diets. This study will thereby potentially provide new targets for intervention of human obesity. PUBLIC HEALTH RELEVANCE: Obesity has reached an epidemic stage and created serious public health problems in the United States. Genetic factors are strongly involved in the development of obesity, most likely in the form of interactions of multiple genes with obesity-promoting environments, such as high fat diets. Knowing the metabolic mechanism and molecular basis underlying the obesity associated with the susceptibility gene, tabw2 in mice, which we propose in this study, will provide new insights regarding obesity genes and pathways that could be tested in humans.